Cerebellum-Cerebrum Dynamics During Gaze Processing in Schizophrenia: Evidence for Social-Cognitive Modulation and Associations with Social Functioning Across Independent Samples

Background: Individuals with schizophrenia have prominent impairments in social cognition that contribute to poor functional outcomes. Gaze processing – the social-cognitive ability to accurately perceive human eye gaze direction – is similarly abnormal in schizophrenia and associated with social functioning. Though gaze processing has known neural underpinnings in cerebral social-processing brain regions, emerging data suggest that the posterior cerebellum plays a key but often neglected role in social-cognitive function. Elucidating the bi-directional cerebellum-cerebrum dynamics underlying social cognition is critical to identifying a novel treatment target. Methods: 39 individuals with schizophrenia and 33 non-clinical control (NCC) participants completed an eye-contact detection task during functional magnetic resonance imaging. Dynamic causal modeling was used to delineate the dynamics between posterior cerebellum (Crus II) and three cerebral social processing nodes (inferior parietal lobule, anterior insula, and fusiform gyrus) regions and to quantify abnormal effective connectivity in SZ. A confirmatory replication analysis using an independent sample (SZ=27, NCC=22) was conducted to confirm the results. Results: Model structure comparison revealed overwhelming evidence that cerebellar connections to cerebral social processing nodes are vital to explaining gaze processing in NCC (ln(BF)=98.84) and SZ (ln(BF)=46.85). Relative to NCC, SZ showed less upregulation of cerebellar outputs during gaze processing (t(68)=2.853, p=.006) and this decreased upregulation was associated with social dysfunction (ρ=-.251, p=.034). These results were replicated in the independent sample. Conclusions: Replicated across two independent samples, people with schizophrenia have altered cerebellum-cerebrum dynamics during gaze processing that is linked to social functioning. Given the accessibility of the cerebellum from the scalp for non-invasive brain stimulation relative to many cerebral social-cognitive regions, our findings have critical implications for translational interventions.